The research proposed here addresses the identity of novel epithelial cells in blood and bone marrow. Epithelial cells identified by cytokeratin expression usually cover body surfaces (like epidermis) or line spaces (like the linings of the gastrointestinal and respiratory tracts). However, research has identified cytokeratin+/EpCAM+ bone marrow derived epithelial cells (BMDECs) in ?normal, healthy? murine and human subjects. To our knowledge, no one has performed functional analyses and characterization of these cells. This is a significant gap in our knowledge of epithelial biology with ramifications towards human health, particularly with regard to conditions where hair follicle or epidermal stem cells have been damaged or destroyed; in instances of chronic inflammation; or in squamous cancers where we know they can function as tumor initiating cells Moreover, these blood borne epithelial cells currently interfere with liquid biopsies as ?contaminating? cells. We therefore hypothesize that BMDECs include a novel population of progenitors that can be recruited to chronically compromised epithelium and regenerate it. Our specific aims are to analyze these cells in vitro and in vivo using strategies that my laboratory and others have developed for identifying epithelial stem cells in hair follicles and epidermis. The significance of functional analysis of BMDECs will contribute to understanding epithelial biology and hematology in general, to the validation of liquid biopsy as a diagnostic tool in cancer research, and help us to achieve our ultimate goal of preventing, diagnosing, and curing chronic cutaneous diseases including cancer and epidermolysis bullosa. The scientific premise supporting this hypothesis is predicated upon: 1) RT-PCR detection of traces of cytokeratin expression in blood and bone marrow of ?normal?, healthy human subjects; 2) similar literature reporting rare BMDECs recruited temporarily to the cutaneous epithelium upon acute injury in mice; 3) several high quality case reports; and 4) our own Preliminary Data demonstrating recruitment of BMDECs to a subset of squamous papillomas in mice; and our documenting the presence of BMDECs in ?normal? adult mice by four different methods. Therefore, to test our central hypothesis and thereby achieve major milestones towards our ultimate goal, we will answer the following questions. Do BMDECs have phenotypic characteristics of epithelial stem cells? And Do BMDECs behave as epithelial stem cells? Converging evidence suggests that BMDECs are multipotential epithelial progenitors, and because they are likely multipotential epithelial progenitors they could be used in regenerative medicine and in circumstances where the tissue stem cells are chronically compromised. Therefore, this research has the potential to move forward the fields of cutaneous biology, hematology and epithelial biology in general. This is a completely new direction of research that will lead to new sources of funding to determine the mechanism of BMDEC recruitment as well as how to modulate their recruitment.